Volume 43 Issue 6
Nov.  2022
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Rong-Jun Ni, Tian-Hao Gao, Yi-Yan Wang, Yang Tian, Jin-Xue Wei, Lian-Sheng Zhao, Pei-Yan Ni, Xiao-Hong Ma, Tao Li. Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway. Zoological Research, 2022, 43(6): 989-1004. doi: 10.24272/j.issn.2095-8137.2022.278
Citation: Rong-Jun Ni, Tian-Hao Gao, Yi-Yan Wang, Yang Tian, Jin-Xue Wei, Lian-Sheng Zhao, Pei-Yan Ni, Xiao-Hong Ma, Tao Li. Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway. Zoological Research, 2022, 43(6): 989-1004. doi: 10.24272/j.issn.2095-8137.2022.278

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

doi: 10.24272/j.issn.2095-8137.2022.278
Raw data were deposited in the National Center for Biotechnology Information database under BioProjectID PRJCA012231, Genome Sequence Archive under Accession No. CRA008352, and Science Data Bank under DOI: 10.57760/sciencedb.03000.
The authors declare that they have no competing interests.
R.J.N. was involved in apparatus design, behavioral tests, data interpretation, and manuscript writing. T.H.G., Y.Y.W., and Y.T. were involved in apparatus design and behavioral tests. J.X.W., L.S.Z., and P.N. were involved in data analyses. X.H.M. and T.L. were responsible for experimental design and revision of the manuscript. All authors read and approved the final version of the manuscript.
Funds:  This study was supported by the Key Project of the National Natural Science Foundation of China (81920108018 to T.L. and P.S.), Ministry of Science and Technology of the People's Republic of China (2022ZD0205200), Natural Science Foundation of Sichuan Province (2022NSFSC1607), Key R & D Program of Zhejiang (2022C03096 to T.L.), Special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001), and Project for Hangzhou Medical Disciplines of Excellence & Key Project for Hangzhou Medical Disciplines
More Information
  • Corresponding author: E-mail: litaozjusc@zju.edu.cn
  • Received Date: 2022-09-15
  • Accepted Date: 2022-10-17
  • Published Online: 2022-10-18
  • Publish Date: 2022-11-18
  • Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.
  • Raw data were deposited in the National Center for Biotechnology Information database under BioProjectID PRJCA012231, Genome Sequence Archive under Accession No. CRA008352, and Science Data Bank under DOI: 10.57760/sciencedb.03000.
    The authors declare that they have no competing interests.
    R.J.N. was involved in apparatus design, behavioral tests, data interpretation, and manuscript writing. T.H.G., Y.Y.W., and Y.T. were involved in apparatus design and behavioral tests. J.X.W., L.S.Z., and P.N. were involved in data analyses. X.H.M. and T.L. were responsible for experimental design and revision of the manuscript. All authors read and approved the final version of the manuscript.
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